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PRESENTED BY 



INFLAMMATION 

BY 
DR. W. G. MacCALLUM 







BEAUMONT FOUNDATION 

ANNUAL LECTURE COURSE 1 

1922 



THE BEAUMONT 
FOUNDATION LECTURES 



SUBJECT 

INFLAMMATION 



BY 
W. G. MacCALLUM 

PROFESSOR OF PATHOLOGY, JOHNS HOPKINS UNIVERSITY 



SERIES NUMBER ONE 



AUSPICES OF THE WAYNE COUNTY 
MEDICAL SOCIETY 

DETROIT, MICHIGAN 
1922 



Dedicated to the 

Members of the Wayne County Medical 
Association who gave service for their 
country in the World War. 

JAMES A. MacMILLAN 

Chm. Patriotic Committee 

JAMES E. DAVIS 
President W. C. M. S. 

gift 

Society 

OCX 31 1321 



PREFACE 

This monograph is the first of the Beaumont Foun- 
dation Lectures, given under the auspices of the Wayne 
County Medical Society on the thirtieth and thirty- 
first of January 1922, by William G. MacCallum, 
Professor of Pathology Johns Hopkins University. 

This Foundation has been made possible by a fund 
set aside to the purpose of securing for the members 
of the Wayne County Medical Society annual lectures 
on some medical or scientific subject. 

The plan is of noteworthy origin, for at the time of 
our entrance into the World War many of the society's 
members gave their services voluntarily to the cause. 
It became known that a number of these had family 
and other responsibilities requiring urgent financial 
assistance. To meet this need a patriotic fund was 
created by voluntary contributions from the members 
of the Society. This fund was purposeful in helping a 
number of physicians and their families through dark 
and trying situations. The total amount contributed 
grew far beyond the requirements and a very consider- 
able surplus remained after all demands had been 
satisfied. This the contributors redonated to the pro- 
gress of scientific medicine specifying the interest 
accumulation a reserve fund from which annual lec- 
tures should be secured. The Foundation was given 
the name of William Beaumont, in honor of a physi- 
cian, now famous for pioneer research work begun 
at Mackinac, Michigan, in 1822, upon Alexis Saint 



Martin. The clinical and laboratory researches accom- 
plished were epoch making, giving to medicine new and 
valuable data upon gastric digestion forming the basis 
for all subsequent information upon the subject. The 
contribution was of signal importance, for it gave to 
medical science the biologic method of research which 
holds in relation to physiology a position analogous 
to that of dissecting to anatomy. 

Medical history makes an enduring record not only 
of the great discoveries of Beaumont, but also of his 
wonderful devotion to a self -assigned task which he 
persistently followed under most discouraging condi- 
tions and great personal sacrifice. 

The pursuit of truth and devotion to humanity are 
now as then at the basis of the art and science of 
medicine, and it is fitting that we commend the 
patriotism and generosity of the members of the 
Wayne County Medical Society whose contributions 
have provided in this permanent way a valuable asset 
to the medical work of Detroit. 

It is the purpose of the Beaumont lectures to give 
instruction in the medical science and foster inspi- 
ration toward higher ideals. The lectures on Inflam- 
mation contain an orderly statement of the present day 
theories and demonstrated facts authoritatively stated 
and arranged in logical sequence and delivered in 
direct unambiguous phraseology. 

J. A. M. 
J. E. D. 



INFLAMMATION 

Introduction 

Rather than attempt in the beginning any definition 
of inflammation it will be well to review our present 
knowledge of the subject and then in retrospect 
determine its outline. It may be said in advance that 
the conception of inflammation is an abstract one 
separating for consideration from all the endless series 
of inflammatory diseases that process which in princi- 
ple and in the details of its character is common to 
all and in itself uniform in its broader lines. In 
whatever sort of injury, intoxication or infection it 
makes its appearance, we can recognise this process, 
which we name inflammation, as a reaction character- 
istic of the living body and little altered by the nature 
of the injury which causes the disease. It is one of 
many responses to injury at the disposal of the body, 
and useful in its defense. It becomes a part of our 
problem, therefore, to outline this particular reaction 
and in so doing to show its relation to the others. 
It is less a question of determining what features are 
essential to constitute inflammation (Aschoff) and 
more a question of deciding which of all the biological 
responses to injury ought to be grouped apart under 
this heading. 

We think of inflammation then as a complex but 
orderly series of events forming a process well adapted 
to the defense of the body against the effects of an 
injury and evidently evolved and perfected in the 



course of ages by selection and persistence of the 
most effective mechanisms which have arisen for the 
protection of the species. It is purposeful, not of 
course in the sense that the individual plans a reaction, 
but in the sense that through the wasteful phylogenetic 
method of the survival of those only that were best 
protected, the animal organism has acquired a well 
aimed machinery of defense. 

From an historical point of view only two periods 
stand out very plainly after the age long recognition 
of the cardinal features of inflammation which were 
made precise by Celsus. Everyone knew in a general 
way the nature of inflammation and realised fairly 
clearly that it was associated with injuries of some 
sort. Everyone familiarly recognised the redness and 
swelling and heat of an inflamed member and felt the 
associated pain and disablement. John Hunter real- 
ised that while inflammation came with the most 
various injuries it often led to healing, but most per- 
sons even to this day, see little but evil in inflammation 
and strive toward its abatement. 

Yirchow's studies formed on the basis of the new 
cellular doctrine, were the starting point of accurate 
investigations, and Cohnheim's introduction of the 
experimental study of inflammation gave him practi- 
cally all we now know of the process. Since then 
interest has waxed and waned with long intervals — 
curiously it comes in waves and all the old discussions 
are reopened. At present we are at the crest of a wave 
of such renewed interest and the literature — especially 
the German — is full of papers on the subject. It is 
true that many of these have a philosophical character 
and bring relatively few new facts to view, but some 
of them help to make clear our general conception. 



8 



Irritants and Injuries as the Cause 
of Inflammation 

It has become clear from the study of innumerable 
instances of inflammation that there is always an 
underlying cause which is essentially an injury to the 
tissues about which the inflammation develops. We 
need not refer again to the beliefs of past eras when 
inflammation itself was regarded as a disease and 
indeed the most widespread disease in all the world, 
since we have learned that it is always possible to 
take a more comprehensive view of disease and analyse 
more clearly its origin, its progress and its termina- 
tion. Nor need we dwell upon those curious state- 
ments as to the evocation of a true inflammatory reac- 
tion by hypnotic suggestion. In any case, if inflam- 
mation follows in a hypnotised person upon the appli- 
cation to the skin of a cold coin with the suggestion 
that it is red hot, it is the production of an injury 
which we are asked to believe — the inflammation might 
naturally follow. 

Inflammation need not follow immediately upon 
the action of the injury — indeed, a certain time 
usually elapses before it develops fully and soihetimes, 
as in X-ray burns, this delay may be rather long. But 
the delay is rarely such as to make it difficult to be 
sure that they are cause and effect. The variety of 
such injurious agencies is almost infinite. Among 
physical influences it is only necessary to mention the 
forms of mechanical violence which may compress, cut 
or bruise the tissues, extremes of heat or cold which 
can cause the death of cells or when less intense, their 
minor injury, the multifarious forms of light energy 
which injure and disturb cells in many ways and the 
types of radiant energy produced in the X-rays and 
radium which are no longer mere vibrations but 



streams of particulate matter, and finally electricity 
which in various forms can injure and destroy tissue. 
Chemical agents of injury and destruction are even 
more varied and numerous and if we include among 
them the substances emitted by bacteria in the course 
of infections, their name is legion and their importance 
overwhelming. 

But to all these injurious agents in their local 
action upon a tissue, the inflammatory reaction is 
scarcely specific. While there are some variations we 
are impressed by its uniformity under all conditions 
and we are impelled to ask whether after all it is 
primarily the injurious agent which causes the onset 
of inflammation, or the more invariable injured tissue 
itself. Nevertheless there are characteristic peculiari- 
ties in inflammations which are sometimes sufficient 
to suggest the character of the injurious agent and 
allow us to conclude with some certainty from the 
changes produced^ that this or that form of irritant 
was at work. Still, this depends chiefly upon the char- 
acter of the primary injury produced and very little 
upon changes in the inflammatory reaction and if we 
can distinguish a pneumonia caused by a virulent 
hemolytic streptococcus from another caused by a 
pneumococcus, it is chiefly because of the extremely 
rapid destructive effect of the former organism, or if 
we can recognise the change in the mucosa of the 
stomach caused in one case by carbolic, in the other by 
sulphuric acid, it is less because of the character of 
the inflammatory reaction than because of the differ- 
ence between the direct effects of these acids on the 
tissues. 

The action of injurious agents in producing inflam- 
mation is a local action — and involves actual injury 
to the tissues. If a chemical substance such as hydro- 
chloric acid be introduced in concentrated form into 

10 



the stomach, it injures the mucosa and excites inflam- 
mation but if it be so diluted as to resemble the gastric 
juice the whole quantity may doubtless be swallowed 
with perfect impunity. It is the local injury of the 
tissues which is essential to the explosion of the inflam- 
matory reaction — and if through some other defensive 
reaction the injury is warded off — if the strong acid 
is washed or wiped away before the injury is effected — 
no inflammatory response follows. 

It seems that the inflammatory reaction is not 
always commensurate wjifr the injury and in this 
respect we -meet with many difficulties which are not 
easy to explain away. A cinder in one's eye will stil- 
us a more intense inflammation and more discomfort 
and pain than necessarily comes to one from the ampu- 
tation of a leg by a competent surgeon. A blood vessel 
may be opened aseptically and half the blood drained 
away with little or no inflammatory protest to such 
an extreme injury although a few bacteria which 
reach the tiny wound may start a most violent reac- 
tion. 

It seems that we have not yet adequately analysed 
the characters of these injuries which make for an 
inflammatory reaction. That they depend on the char- 
acters of the injurious agencies is obvious enough and 
the difficulty seems to lie to some extent in the sepa- 
ration of the local injury from the general one. But 
more especially it seems possible that there may be a 
distinction between injury and irritation. Usually 
both are present at once and one may mask the other. 
Thus a hot iron applied to the skin is intensely irritant 
and destructive at the same time. Mustard oil is some- 
what destructive and very intensely irritating and its 
action on the skin is followed by an injury of moderate 
character and a very acute inflammation. Pure car- 
bolic acid is also destructive, but while causing a deep 

11 



necrosis of the skin, anaesthetises it and is slowly 
followed by an inflammation which is less stormy than 
that produced by mustard oil. 

Is it possible that the irritation which is felt by the 
nerves is capable of intensifying the inflammatory 
response, and is a painful injury more likely to be 
followed by inflammation than a painless one which 
destroys more tissue? The discussion of this question 
which cannot be very clearly answered, must be merged 
later with that of the part played by the nervous 
system in the reaction itself. 

Direct Effects of Inflammatory Irritants 
upon Cells 

It must be evident that in their action upon the 
tissues the injurious agencies which evoke inflam- 
mation must vary not only quantitatively but in the 
quality of their effects. Usually this effect radiates 
somewhat from the immediate point of impingement 
upon the tissue and becomes weaker and weaker as 
one passes out into the neighboring region. Every 
degree in intensity of the injury can be observed, there- 
fore, in the margin of such an area and in many cases 
one can see the whole gamut of resulting alterations 
in the cells, from complete destruction in the centre 
to mild or fading disturbances of nutrition or functiOD 
as the normal unaffected tissue is approached. Often 
the injury is so slight although followed by an intense 
inflammatory reaction, that it is difficult to see the 
direct effects in any cells. In many cases so few cells 
are actually killed that Neuman has suggested the 
term micronecrosis to express this condition. Even 
here, however, if the ultimate fate of these cells can 
be easily observed, their death becomes more obvious. 
A sunburned arm shows at first no clear proof that 

12 



cells have been killed but later when the surface skin 
peels off we know that those cells at least have been 
destroyed. 

Interference with the life processes of cells may 
affect their function, their nutrition or their power of 
growth and division. Borst in his excellent paper, 
makes an effort to consider these separately and 
emphasises the importance of the integrity of the 
functional activity of the cell in the maintenance of 
the other activities. jThe most severe injury produces 
immediate death or the cell — anything short of this 
leaves the cell alive perhaps to die later or to live in 
a disabled state. Injuries of intensity sufficient to 
cause death of the cell may yet vary in quality so that 
while some, such as the application of a hot iron or 
pure carbolic acid coagulate the whole protoplasm at 
once, others may kill the cell without themselves pro- 
ducing coagulation. It is far more difficult to be sure 
that the life of a cell has ceased without coagulation. 
We cannot readily determine, for example, whether 
potassium cyanide in killing a cell has any coagulating 
effect because a cell, however killed, quickly becomes 
coagulated or causes the coagulation of the tissue 
fluids which permeate it by virtue of the ferments 
which it now liberates. 

All functional and other cell activity stops with this 
fixation and the cell is as it were arrested as though 
suddenly petrified in what we have become accustomed 
to consider its normal state in our microscopical prepa- 
rations of fixed tissues. In a man who had died 
promptly from the effects of swallowing a large 
amount of pure carbolic acid, the whole stomach was 
white and coagulated but in sections its mucosa pre- 
sented the ideal picture of perfectly normal tissue. 

When the coagulated cell remains surrounded by 
living tissue, however, protein-dissolving ferments 

13 



quickly change it so that the nucleus no longer takes 
the stain and the whole architecture of the cell is 
rapidly disintegrated. Dead cells thus soon melt into 
formless masses even when the injury itself does not 
mangle or deform them. 

Less severe injury which does not interrupt the 
life of the cell also does not coagulate it but disturbs 
all its functions. Evidences of functional activity are 
not easy to observe unless we watch living cells. It is 
true that specific secretory granules should form an 
index of one sort of function but changes in them, 
as well as changes in the bulk of the cell, and the 
accumulation of other granules of questionable nature 
are hard to interpret. 

Cloudy Swelling. — The whole question of cloudy 
swelling or parenchymatous degeneration conies to the 
fore at this point and must be discussed if only because 
of the part it has played in the history of inflamma- 
tion. Virchow described it as an essential and promi- 
nent feature of inflammation. He saw in injured tis- 
sues when studied in the fresh condition, that the cells 
become greatly swollen and their special features 
such as the striated borders of the renal epithelium, 
obscured on account of the abundant accumulation of 
fine granules of protein substance in the cytoplasm. 
This he regarded as an accumulation of nutritive 
materials in the cell. For him inflammation was a 
disturbance of nutrition affecting especially the cells, 
which attracted nutritive substances to themselves. A 
fluid protein containing exudate accumulated between 
and in the cells, producing in both places the swelling 
which in an inflamed area becomes evident to the eye. 
In this exudate and between the cells new cells formed 
which were leucocytes. This theory has been aban- 
doned but its main idea, that upon injury, the cells of 
the tissue actively respond and defend themselves, 

14 



swelling up and accumulating protein granules and 
fluid, has continued to interest some investigators who 
even now attempt to resuscitate the idea of a paren- 
chymatous inflammation, in which the changes in the 
fixed cells are to be interpreted as the expression of 
their energetic attempt to defend themselves and the 
other cells against the damage. 

But nearly all pathologists look upon these changes 
as retrogressive in character — the effects of the injury 
sometimes ending in disintegration of the cell but 
often less severe and fading away with the recovery 
of its full function, v. Hansemann dwells particularly 
upon the importance of a proper understanding of 
cloudy swelling which he thinks has been greatly 
neglected but he does not revert to the theory of its 
paramount interest as an active process. He explains 
that the "tropjige entmischimff" of Albrecht is some 
thing quite different and that one can observe the 
true cloudy swelling only in teased preparations or 
frozen sections of fresh unfixed tissue. Fixed tissue is 
confusing, for even formalin contains enough acid to 
dissolve these granules promptly and to produce by 
coagulation other granules which may be mistaken for 
them. Marchand, on the other hand, would abandon 
the term cloudy swelling as having no precise mean- 
ing since much of the granular material found in cells 
is due to post-mortem changes, other granules are 
really minute fat droplets, while the condition in one 
organ may represent something quite different from 
what in another organ produces the same appearance. 

Most interesting in this regard because based on a 
really trust- worthy method of study, are W. H. Lewis' 
observations upon the granules which appear in dying 
cells in tissue cultures. These are minute or larger 
granules arranged chiefly about the centriole often in 
vacuoles and staining red with neutral red, while the 

15 



mitochondria take none of this stain but are colored 
by Janus black. He regards them as waste products 
of the cell and not as enclosed food particles. K. 
Prigosen, working under Lewis, makes similar observa- 
tions for other cells under abnormal conditions which 
lead to their degeneration. 

It is scarcely possible to be quite sure that these 
granules correspond exactly with those seen in cloudy 
swelling but the thought suggests itself and if one 
transfers their conclusions to this condition it would 
seem that in cloudy swelling one might regard the 
granules as waste products not especially indicating a 
disturbance of the function of nutrition to which some 
authors have ascribed an accumulation of unused food- 
stuffs within the cell. 

Fatty Degeneration. — It is not any more simple to 
decide as to the relation to the functional capacity of 
the cell of the excessive amounts of visible fat in the 
form of globules which are so often found in injured 
cells. The divergent opinions about this are well 
known and it has always seemed more rational to 
suppose that in an injured cell the ability to digest and 
utilize fat naturally brought to it is impaired and 
that therefore the fat is formed at the expense of the 
cytoplasm. There is, of course, the view that since it 
is well known that the tissues contain much fat in 
invisible form, its occurrence in globules is merely a 
collection and rendering visible of fat already present 
(fat phanerosis). At any rate, there is practically 
no doubt that in injured cells the fat becomes con- 
spicuous as an evidence of injury and persists even if 
the injury progresses to the death of the cell. But that 
such cells need not die is evident from observed 
recoveries and from the fact that in a liver in which 
a zone of each lobule is rendered necrotic by some 
poison, the cells of adjacent zones become loaded with 

16 



fat, and it is precisely in those less injured fat hold- 
ing cells that regenerative mitoses are seen. 

Other paraplasmic substances such as globules of 
hyaline or fibrinoid material may accumulate in large 
swollen and injured cells. Vacuoles without any con- 
tent other than fluid may also appear. Glycogen in 
increased quantities in the less deeply injured cells 
is an accompaniment of the inflammatory reaction 
(Best). 

Interpretation of Effects of Injuries. — The signifi- 
cance of all these accumulated materials is in each 
instance difficult to decide. We know that they accom- 
pany injury but it is not perfectly clear whether they 
are passively collected as the result of a degradation 
in the functional capacities of the cell or possibly 
evidence of an attempted active response on the part 
of these cells — a defensive response against the injury. 

To me it appears that the evidence is overwhelm- 
ingly in favor of the view that they are merely signs 
or indications of injury associated with other and 
more unmistakable evidences of injury as time passes 
and the cell proceeds to disintegrate. Evidences of 
active response exist, it is true, in the rapid growth 
and reproduction of the leucocytes and possibly there 
may be a new formation of other more locally formed 
cells with a defensive significance. This, however, is 
the most bitterly debated question in the whole story 
of inflammation and must be deferred to a later point. 
Epithelium, muscle, nerve cells, etc., seem little if at 
all specialised toward defensive activities and although 
they show signs of regeneration after injury they pro- 
ceed timidly and only after the way has been cleared 
of danger. 

Retrogressive changes are produced, also, in the 
more hardy elements upon which these cells rely for 
their defense — in the blood-vessels, the connective 

17 



tissue and in the leucocytes, and like the others, they 
die or degenerate and the capillaries are obliterated, 
but the next ranks are still alive and active in spite 
of slighter injuries. 

Direct effects of injuries thus vary in intensity and 
extent with the nature of the injurious agent and with 
the degree to which it is allowed to act. In the case 
of bacterial infections the injury may grow in pro- 
portion with the failure of defense so that the invasion 
of bacteria promptly halted by the tissues of a normal 
person before the bacteria have an opportunity to 
multiply, becomes in a weak old man an overwhelming 
spread of bacteria throughout the body, and a hope- 
less rout for the defense. 

General illness following an injury must be regarded 
as the direct effect of the injury and cannot be ascribed 
to the defensive reactions, inflammation, fever, etc.. 
This will become clearer as these reactions are de- 
scribed. 

The Inflammatory Process 
In a general way everyone is familiar with the 
appearances of inflammation, with the redness and 
irritation and tenderness or actual pain in the hot 
swollen place, and everyone looks for a cause of one 
sort or another. But to search beneath the surface 
and to analyse into its elements this peculiar and 
complex change has required the concentrated study 
of many years with many problems still left unan- 
swered. Virchow attempted it as related above, with 
the result that he found the fluid exudate among the 
cells with many leucocytes and a swelling of the cells 
with abundant granules in their cytoplasm. He recog- 
nized the hyperemia but thought the leucocytes were 
formed by multiplication between the fibres of the 
tissue and that the swollen cells were of all things 
most active in this process. 

18 



The Vascular Reaction. — It was then that Cohnheim 
conceived the idea of exposing transparent vascular 
tissues such as the mesentery of the frog, or its tongue, 
from which the epithelium had been stripped off, to 
continuous observation under the microscope and 
quickly discovered the marvellous happenings which 
have ever since been so familiar to all who study 
inflammation. It may be wearisome to have all this 
rehearsed but without it we can scarcely proceed to 
any of the details which have since been added. 

The mere exposure to air is sufficient to irritate and 
injure the mesentery of the frog so that inflammation 
begins very soon but with such a tissue as the web of 
the frog's foot or the wing of a bat it is necessary to 
apply an irritant to attain the same result. Too severe 
an injury will cloud the view because it may produce 
too profound changes in the tissues and blood vessels, 
so that the circulation is stopped in the field of obser- 
vation and the tissue dies — it is then only in the sur- 
rounding areas, sometimes quite far away, that the 
process of inflammation is clearly to be studied, and 
with the mesentery of the frog, and far more with the 
mesentery or omentum of a warm-blooded animal, 
great care must be used to protect the tissue against 
drying and against extremes of temperature lest the 
injury be too complete. 

The circulation in arteries, capillaries and veins can 
be seen with great clearness and its rate and volume 
easily observed. The arterial blood goes rapidly in 
pulsations but through the capillaries and on into the 
veins it is slowed into a steady stream in which one 
may see that the flowing cells maintain a central or 
axial position everywhere separated from the wall by 
a zone or layer of clear plasma. The surrounding con- 
nective tissue cells and fibres are in their normal rela- 
tions. Very soon it is realised that the stream is hurry- 

19 



ing at a more rapid rate and that the arterioles and 
venules have widened noticeably. The blood rushes 
through the dilated capillaries and into the venules 
so fast that there is no possibility of recognising in 
the yellow stream any separate cells. But then, with 
a further widening of these vessels and the appearance 
of new wide capillaries which were invisible before, 
the voluminous stream begins to go more slowly and 
still more slowly until one may actually see tne red 
corpuscles as they pass. In some channels it may even 
stop for a time only to move on again or finally to 
come to rest. But in general, apart from such minute 
stases, the stream goes on slowly and one can see that 
in the plasma zone against the vessel wall there collect 
leucocytes which roll along, sometimes sticking to 
the endothelium and being dislodged. A glance at the 
connective tissue outside the vessel shows that a 
change has taken place there, for now the cells and 
fibres are spread apart by fluid which has collected 
between them having filtered out through the walls of 
the capillaries. 

Emigration of Leucocytes. — Continued watching 
shows, as Cohnheim described it, somewhere along the 
wall of a minute venule a tiny projecting point of clear 
protoplasm which grows until finally it pulls itself 
aWay from the wall and drops apart as a rounded, 
glistening cell — nothing other than a leucocyte, it 
moves away a little and many others worm their way 
out through the wall in the same way and accumulate 
about the vessel or near it. This, the emigration of 
the actively motile leucocytes, is the crux of the whole 
beautiful observation but from the way he describes 
the effect of stopping the flow of blood in checking the 
emigration, it seems that Cohnheim did not clearly 
recognise the independent activity of these cells but 
thought they were forced out by the pressure of the 

20 



moving stream. This explanation he applied to the 
red corpuscles too which may follow out in small 
numbers in the wake of the leucocytes. When the 
injury is very severe and the stream tends to stop, 
there is no chance for the selection from the blood of 
the relatively less numerous leucocytes and a great 
excess of red corpuscles is extrava sated— this is the 
hsemorrhagic inflammation that comes with some very 
intense bacterial infections. 

The Exudate. — Thus, there are now among the cells 
and fibres of the tissue many leucocytes and perhaps 
a few red corpuscles which are left quite near the 
vessels while the leucocytes wander farther afield. 
Being injured, the cells furnish a ferment to the 
coagulable fluid and a delicate meshwork of fibrin 
appears among the separated fibres of the connective 
tissue. With the aid of staining methods or even in 
the living tissue, one can see a few other cells loosely 
scattered in this oedematous tissue which vary in size 
but differ from the leucocytes in having a single 
rounded nucleus and few cytoplasmic granules. These 
monunuclear cells which seem to wander in from the 
neighboring tissue are few at first but in protracted 
inflammations become very numerous. 

Thus we have a new condition in which the whole 
vascular bed is widened, blood is brought in increased 
quantities to the part and much of the contents of the 
vessels is poured out to bathe the injured tissues. 
These changes quite readily explain the cardinal symp- 
toms of inflammation — the redness, the swelling and 
the heat of the inflamed place which, from being so 
flooded with blood, assumes the temperature of the 
interior of the body. 

Discussion of the Factors in the Inflammatory 

Process 
The Hypercemia. — The first phenomenon which re- 

21 



quires explanation is the active hyperemia which can 
perhaps be separated although by no very sharp line, 
from the later hyperaemia in which the vessels seem 
paralysed. It is marked by a rapid stream through 
somewhat widened channels and one might think of 
it naturally as a vasomotor phenomenon through irri- 
tation of the nerves. Much interest has been centred 
in the relation of the vascular changes in inflammation 
to the nervous system in recent years but even yet this 
relation is not perfectly clear. I myself found that if 
the leg of an animal were completely amputated and 
then replaced by anastomosis of the large vessels and 
suture of the other tissues so that one might be certain 
that all nerves of whatever character were cut, the 
application of mustard oil produced inflammation of 
quite as pronounced character in the amputated leg 
as in the normal one. It appeared at the same time 
and was if anything slightly more intense. A. Mnian 
Bruce confirmed this and ascribed the vascular widen- 
ing still to a vasomotor effect produced as an axone 
reflex by which he meant that sensory stimuli were 
transferred to efferent vasomotor fibres at some point 
along the sensory nerve axone without recourse to the 
brain or cord. He found, however, that if the nerves 
be allowed to degenerate after section, no such arterial 
hyperaemia occurred. So, too, Breslauer found that 
the initial active hyperaemia followed for a time after 
the nerves were cut but later, after the nerves were 
degenerated, failed to appear upon the application of 
the irritant. General anaesthesia had no effect upon 
the appearance of this hyperaemia but local anaesthesia 
abolished it. In contradiction of Spiess' results he 
found that the central appreciation of pain from peri- 
pheral stimuli had nothing to do with inflammation. 
On the other hand, Groll finds that the reflex pro- 
duction of hyperaemia plays no part — the appearance 

22 



of an irritative arterial hyperemia is not interfered 
with by nerve section even with degeneration. The 
nervous system affects the inflammation only indirectly 
by affecting the circulation, and the changes in the 
inflamed area are due to direct action of the irritant. 

Thus, it seems that the ideas about the relation of 
the nervous system to the dilatation of the arterioles 
and capillaries in inflammation are very contradictory. 
Certainly inflammation in its more essential phase of 
capillary paralysis is not affected by isolation from 
the nervous system even when the nerves have degener- 
ated and it is questionable whether such complete 
exclusion of the nerves affects a rather hypothetical 
earlier stage of active hyperemia. The authors lean 
rather to a direct irritation of the vessel wall perhaps 
through the intermediation of local nerve endings in 
the wall itself. 

Of course the experiments of Samuel have shown 
that the profound vasoconstrictor limitation of the 
circulation of a rabbit's ear which follows section of 
the auricular nerves leaving the sympathetic nerves 
intact, persists so that the effect of a burn is necrosis 
and not inflammation, while the reverse section of the 
sympathetics which leaves the vasodilators of the 
auricular nerves free to maintain a great flushing 
of the ear, rather favors a violent inflammatory reac- 
tion after scalding. 

The attempt to define the effect of the vasomotor 
nerves upon the hyperemia of inflammation which has 
led to the separation of an active arterial hyperemia 
from a paralytic passive widening of the capillaries, 
ends rather lamely in the assumption of a localised 
nervous mechanism in the vessel walls. There is much 
proof, however, (Krogh) that the walls of the arteri- 
oles and more particularly those of the capillaries, 
have an important independent tone and contractility 

23 



so that the effect of the irritant may well be direct and 
without the intermediation of any nervous mechanism 
and further that it may well be a direct chemical 
influence. The work of Dale and his colleagues upon 
shock showed clearly that the enormous dilatation of 
the capillaries which produces a partial stagnation of 
the blood in the widened channels, is or may be due to 
histamine, a derivative of the protein of injured tissues. 
We thought it might be possible that the widening of 
the capillaries in inflammation could also be explained 
as the effect of a substance like histamine or histamine 
itself upon their walls and the adjacent injured tissue 
might well constitute a source of this histamine. Dr. 
Rich therefore studied the effect of histamine upon 
the capillaries and proved that when locally applied, 
or when injected into the circulation, it does widen 
the capillaries greatly, bringing into prominence many 
which were invisible before. He did not apply this 
result directly to inflammation but it seems to be a 
very plausible explanation for the paralytic condition 
of the capillaries found there. The rapidity of its 
action makes the distinction between a stage of arterial 
hyperemia and one of paralytic hyperemia seem 
rather questionable. 

Dr. Rich's experiments showed that any attempt 
to examine and measure the capillaries by spreading 
out the omentum resulted in a maximal dilatation and 
paralysis of the capillaries no matter how carefully 
the tissue was protected and that the effect of hista- 
mine could be shown only in the omentum which had 
never been so exposed. This makes one question a 
little the accuracy of the generally accepted observa- 
tions upon the slowing of the blood stream in inflam- 
mation. These observations have been made very 
largely in exposed tissues where extreme injury might 
well occur, and are rather inconsistent with the 

24 



familiar hot rush of blood through an inflamed area 
and also with the observation that an incision into an 
acutely inflamed tissue allows the escape of arterial 
and not venous blood. But there is at least no question 
that in these exposed tissues the process of emigration 
of leucocytes occurs only after the visible slowing of 
the stream and it seems difficult to believe that it 
could occur to the same degree if the initial rapidity 
of the stream were maintained. 

The widening of the capillaries brings into plain 
view channels filled with blood which were previously 
invisible and existed doubtless as collapsed tubes of 
endothelium. The application of adrenalin appears 
to have no effect in contracting the vessels of an 
inflamed tissue and lessening the content of blood, nor 
has it in the case of the tissue poisoned with histamine. 
It appears, as was pointed out by Dale and Laidlaw 
that this widening is really due to a paralysis of the 
otherwise active endothelial cells which causes them 
to relax their tone and allow blood to pass and 
accumulate in much greater volume than before. The 
gradual resumption of their tone after the waning of 
the inflammatory process leads once more to their 
narrowing and in many cases to their disappearance 
from view. 

Changes in Capillary Walls. — It seems that this 
paralysis is accompanied by other changes in the capil- 
lary wall which are recognisable only by their effects. 
The leucocytes now adhere as they pass and are only 
dislodged by the violence of the stream, finally remain- 
ing attached at a point at which, by forcing a pseudo- 
pod through the wall between two endothelial cells, 
they ultimately make their way out. It has been shown 
that the silvered endothelium in this condition shows 
broader lines between the endothelium than in the 
normal capillaries but we cannot recognize morpho- 

25 



logically any more significant change. Nevertheless 
the wall becomes much more permeable for fluids and 
for the proteins of the blood, since the fluid of an 
inflammatory exudate is much richer in protein and 
more readily coagulable than the transudate which 
appears without inflammation. The emigration of the 
leucocytes is aided in the slower stream by their 
lightness which allows them to separate themselves 
from the heavier axial stream of red corpuscles and 
flow along in the marginal zone of plasma. The change 
in friction between the altered endothelium and the 
plasma which is used as an explanation of the slowing 
of the stream may also facilitate the adhesion of the 
leucocytes. They force their way out eagerly and in 
all their movements are guided by the attraction 
exerted by the diffusion of some chemical substance 
from the injured tissue or from the injurious agent 
itself (chemotaxis). Their approach to this dead or 
injured tissue is otherwise incautious because they 
often come too near and are themselves injured or 
destroyed. When the source of attraction is merely 
a mass of dead tissue they penetrate its margins but 
are automatically brought to a stop by lack of oxygen. 
In diffuse forms of inflammation in which the injury 
has not been concentrated the exudate is found 
throughout the tissue. 

Increased Temperature of Inflamed Part. — These 
changes explain fairly easily as remarked above, the 
swelling and redness of the inflamed tissue. The 
heightened temperature of the part is ordinarily 
thought to be due to the rapidity of the flow of blood 
which passes before it can be cooled and thus brings 
to the surface the temperature of the interior of the 
body. The inconsistency of this with the idea of slow- 
ing of the stream in the widened capillaries has 
already been suggested. Several writers and most 

26 



recently Segale, have tried to show that there is an 
increased local metabolism which is responsible for 
some heat production in inflamed tissues but this 
seems not entirely convincing and would at most 
account for only part of the heightened temperature. 

Pain in Inflammation. — As to the pain apart from 
that caused at first by the direct action of the irritant 
we have no very satisfying explanation. Tension of 
the tissues would appear to play a great part since 
the relief of tension by incision of an abscess usually 
brings relief of pain. It is objected that tension pro- 
duced in the interstitial injection of fluid is part of 
the method of local ana3sthesia and that the pain in 
inflamed and swollen tissue must be due to irritation 
of the nerves by the inflammatory irritant. 

Bittler thinks the pain due to insufficient vasomotor 
relaxation and perhaps the supposed relief from the 
application of heat to an inflamed area falls in with 
this idea, but in a tissue in which the arterioles and 
capillaries are widened to their utmost, vasomotor 
relaxation seems hardly capable of being pushed 
further. 

Composition of Inflammatory Exudate. — At first 
the inflammatory exudate outside the vessels is rather 
simple — a fibrinogen containing and therefore coagu- 
lable fluid which soon shows interlaced fibrillar of 
fibrin, neutrophile leucocytes and a few red corpuscles 
together with a few lymphocytes. Later if the inflam- 
mation is protracted by the persistent pressure of the 
irritant, as is so generally the case, there arrive other 
freely wandering cells which are by no means so 
clearly derived from the blood in the blood vessels but 
seem to have wandered into this region from some- 
where in the neighborhood. These are in great part 
mononuclear cells varying in size and in their other 
characters. Most of them are usually larger than 

27 



lymphocytes with a more vesicular nucleus and cyto- 
plasm which is nongranular or contains a few baso- 
philic granules. These are the mononuclear wandering 
cells, monocytes, histiocytes, clasmatocytes or poly- 
blasts of various authors. Mallory has called them 
endothelial leucocytes. In somewhat later stages 
plasma cells appear as oval or elliptical, smoothly out- 
lined cells whose nucleus with deeply staining clumps 
of chromatin is placed usually at one end while the 
cytoplasm takes a bluish stain, leaving an unstained 
space about the nucleus. These are related to the 
lymphocytes and of lymphocytes there are usually 
large numbers. 

With such a field for study we must pause for a 
little to ascertain the nature of all the cells concerned 
and the source of those which accumulate in unac- 
customed numbers. We may distinguish at the begin- 
ning cells, which, because they are intimately bound 
up with others of the same sort by intercellular bridges 
or otherwise, remain stationary and form a tissue, 
from another group of freely moving cells which are 
bound by no ties and are either swept along in the 
blood or lymph or wander at will by their own powers 
of locomotion anjwhere in the interstices of the tis- 
sues. The first, the fixed tissue cells, can of course 
divide and stretch out processes and by growth spread 
over a surface or into a scaffolding of fibrin but we 
see little evidence of any power of active wandering. 
The free wandering cells on the contrary can put out 
pseudopodia and travel like amoebae at will. Rather 
they seem to be guided by smell or taste or something 
analogous for they are impelled to move in the direction 
of certain substances which attract them by virtue of 
some chemical influence radiated through the tissues 
for some distance. This is the process of chemotaxis 
which has been so much discussed by Pfeffer and by 

28 



Metchnikoff. Negative chemotaxis is thought of also as 
the repulsion felt by these cells for substances which 
act in the opposite way but there is less convincing 
evidence if its existence. 

The nature and origin of all the fixed cells is very 
clear from embryological investigations. Even the 
most questionable, the lining cells of the peritoneum 
and other body cavities are now universally regarded 
as cells of mesoblastic origin although they participate 
in some of the morphological characters of epithelium. 
This is true of them in far less degree than of the cells 
of the renal tubules which everyone thinks of as epithel- 
ium although they too originate from the early meso- 
blast. It shows that the ultimate form and function 
may be quite far removed from what might be 
expected from the origin. 

Nature of Wandering Cells. — The origin and develop- 
ment of the wandering cells has been the subject of 
interminable dispute and there are still many great 
problems awaiting solution but in general it may be 
said that in the embryo and foetus they arise in very 
many regions — almost everywhere, in fact, from the 
tissues of the supporting framework of the body and 
the blood vessels. After birth it seems that certain 
areas become specialised for their production, among 
which the bone marrow comes to hold a very promi- 
nent place as the chief seat of formation of many of 
the cells of the blood. I shall not attempt to enter 
into the discussions of those who hold to the mono- 
phyletic origin of these cells as opposed to those who 
regard them as of dual or poly phyletic origin. Excel- 
lent, and, indeed, epoch making studies have been 
made by Ehrlich, Maximow, Dantchakow, Marchand 
and others and Pappenheim and Ferrata have collected 
all this information in atlases of the morphology of 
these cells. Such numbers of forms and so many tran- 

29 



sitions with such a variety of details of structure and 
types of granules have been observed that one may well 
become bewildered. This work has been done with 
various ingenious methods of isolating experimentally 
the interesting cells, fixing them and staining in sec- 
tions or otherwise and an almost complete survey of 
their origin and relations has been made. But much 
of the tracing of the relations of cells depended upon 
the finding of transitional forms, which is an uncer- 
tain sort of evidence. We have, therefore, hailed with 
pleasure the work of Dr. Sabin which concerns the 
origin of the cells of the blood and connective tissue 
in the area vasculosa of the embryo chick. The differ- 
ence between this and the other work lies in the fact 
that by watching the growing tissue, living cells specifi- 
cally differentiated by vital stains can be seen and 
followed through every stage of their development. 
One cannot feel any doubt of the correctness of these 
results and it is comforting to find that most of the 
previous work agrees fairly well. The main results 
are as follows : In the undifferentiated mesenchyme 
certain cells in strands separate so as to contain a 
lumen which fills with fluid. These are angioblasts and 
when they thus line a canal are endothelial cells. 
From the endothelial cells by division cells are formed 
which drop into the lumen of the canal and after 
various developmental changes become red corpuscles. 
Other cells arising from the endothelium in the same 
way and dropping into the lumen or becoming strewn 
off to the outside of the endothelial tube become the 
monocytes or large mononuclears and transitionals 
of the blood and the monocytes or histiocytes or mono- 
nuclear wandering cells of the tissue. They are 
apparently identical with the adventitial cells of 
Marchand, the polyblasts of Maximow and the macro- 
phages of Metchnikoff as well as the endothelial leuco- 

30 



cytes of Mallory. It must be remembered, however, 
that this proof of their origin is brought only for 
embryonic tissues as yet. Other cells resembling 
angioblasts but outside recognisable blood vessels, give 
rise to mononuclear granulated cells which become the 
various types of polymorphonuclear leucocytes. These 
quickly make their way into the blood vessels, passing 
between the endothelial cells. Dr. Sabin's work gives 
no idea of the origin of lymphocytes which appear to 
arise within the body of the embryo and not in the 
area vasculosa. We must, therefore, cling as yet to 
the idea of Flemming that they take their origin from 
the germinal cells of the adenoid tissue although 
Marchand in his review describes their derivation from 
indifferent wandering cells of the mesenchyme which 
also give rise to various other types of cell. 

While these things are fairly clear in the embryo 
and we can believe that endothelial cells and angio- 
blast-like cells of the mesenchyme can everywhere give 
rise to the mobile cells of the blood and tissues, it is 
not quite so clear in the adult organism. There we 
know that under normal conditions the formation of 
the red corpuscles is practically limited to the bone 
marrow. This is true also of the neutrophile and 
eosinophile leucocytes. The lymphocytes appear to 
arise in adenoid or lymphoid tissue everywhere but 
we do not yet know precisely where to locate the 
definitive site of formation of the monocytes, that is, 
the larger mononuclear cells of the blood and the 
larger mononuclear phagocytic wandering cells of the 
tissue. Marchand in a former paper referred them to 
the indifferent wandering cells of the mesenchyme, 
but in a more recent one derives many of them from 
endothelial cells. Aschoff and his pupils derive them 
from the so-called reticulo-endothelial cells of various 
tissues, especially the adenoid tissues and spleen and 

31 



the lines between these and the cells of the lymphocyte 
series are not sharply drawn. Dr. Sabin's methods 
seem to show, however, more clearly than ever before 
that the lymphocyte is a cell apart and suggest that 
the embryonic mode of formation of the larger mono- 
nuclear wandering cells may be perpetuated in the 
connective tissues or in some organ such as the spleen. 
All those cells seem to diverge permanently from the 
fixed tissue and assume specific functions which are 
quite different from those of the connective tissue cells. 
The most distinctive are perhaps the granulocytes or 
polymorphonuclear leucocytes with their neutrophile 
or eosinophile granulations. These are so familiar 
that we need refer only to their ability to act as phago- 
cytes and their especial avidity for bacteria — they 
produce, as Opie has shown, a proteolytic ferment 
which acts like trypsin in an alkaline medium. The 
lymphocytes are not strikingly phagocytic nor are 
their peculiar oval derivatives the plasma cells of 
Unna, but the monocytes or mononuclear wandering 
cells exhibit an eager power of engulfing and digest- 
ing, not so much bacteria as the debris of injured and 
dying cells. They, too, produce a ferment which like 
pepsin acts in an acid medium. It seems improbable 
then that the neutrophile leucocytes and the mono- 
cytes could act side by side in one fluid medium. 

Activities of the Exudate. — The inflamed tissue at 
this stage contains much debris of the dead and 
injured cells together with fibrin and often bacteria 
and other foreign particles. All these things form an 
obstruction to the restoration of the tissue to its 
normal state by any process of repair and must be 
removed to the last particle. This is essentially the 
task of the mononuclear wandering cells which as 
ferment producing phagocytes now approach. They 
become especially numerous if the inflammatory reac- 

32 



tion is protracted by the persistence of bacterial or 
other irritation but seldom advance quite into the 
field reached by the neutrophile leucocytes where 
bacteria are active. 

There are many forms and great extremes in size — 
in any old area of inflammation the collection of loose 
cells is really bewildering in its variety and it is little 
wonder that confusion has reigned so long as to their 
relation each to the other. Lymphocytes can readily 
be found in great numbers and among them many 
larger cells with paler nucleus and cytoplasm which 
varies extremely in its abundance. These larger cells 
are most distinctly phagocytic and may often be found 
loaded with the partly disintegrated bodies of other 
cells. Often they contain fat droplets and this is 
usually the case when they have grown to a very 
great size. They have no conspicuous specific granules 
but they may acquire more than one nucleus. Indeed, 
it seems to be from the fusion or incomplete division 
of these cells that most of the foreign body giant cells 
are formed. 

These are the cells which Maximow called polyblasts 
and which he derived from the lymphocyte through a 
process of growth following upon their emigration 
from the blood vessel. But they correspond also as 
already stated with the histiocytes of Aschoff and 
Kiyono and with the endothelial leucocytes of Mallory. 

We are left with a somewhat vague idea that even 
though we know they must be continuously formed 
throughout life and that in the embryo they arise from 
the capillary endothelium, their precise point of origin 
in the adult is not yet proven. Multiplication Dy 
mitosis in situ is often evident and gives one expla- 
nation of their increase. Special irritants attract a 
conspicuous number of other cells such as the eosino- 
phil leucocytes which are abundant in the reaction 

33 



caused by worm parasites or the mast cells with baso- 
philic granules which appear in numbers in some other 
infections. Plasma cells which seem to be regarded as 
closely related to lymphocytes are sometimes in 
chronic inflammations so numerous as to overshadow 
all the others. 

In general, then, we may say that in the acuter 
stages of the inflammatory reaction the polymorpho- 
nuclear leucocytes with their phagocytic avidity for 
bacteria and their trypsin-like ferment dominate the 
field while in more protracted inflammatory reactions 
the mononuclear wandering cells make their appear- 
ance in quantities and by means of their ability to 
engulf the debris of cells and with the aid of their 
pepsin-like ferment act as scavengers and clear away 
all obstructions to repair. 

Significance of Inflammation and Allied Reactions 

The significance of all this which so far represents 
the inflammatory reaction seems on reflection suffi- 
ciently clear. There are numerous reflexes which 
serve to prevent or ward off injury such as coughing, 
sneezing and vomiting. There are also numerous 
mechanical contrivances for the protection of the body 
against injury, better developed in other animals than 
in ourselves. Inflammation differs from these in that 
it is a response to an actual injury which aims at the 
limitation of the injury and the destruction and 
removal of the irritant and of all the dead material 
left behind. It is so orderly in its progress and makes 
use of so many physical and chemical processes, and 
takes advantage so thoroughly of the peculiar fitness 
of such substances as fibrin to serve its ends that one 
can only suppose that such a wonderful mechanism 
must have been evolved in the course of ages through 
the selection of the most useful features of all possible 

34 



reactions by the survival of those animals in which 
they occurred. / 

It would be interesting to learn if we could from the 
fossils of the earliest periods whether inflammation 
existed in those days. We know well . enough from 
Buffer's studies of the mummies of Egypt that our 
familiar inflammation was perfected some thousands 
of years ago but it is pleasing to think that the lack of 
it might have had something to do with the extinction 
of the fearsome mesozoic reptiles. 

Even now after all these centuries it is by no means 
a completely satisfactory process. It seems clumsy 
and our autopsies show how often it fails to prevail 
over the inroads of the injury, how often it brings 
about conditions which, no matter how praiseworthy 
the intention, are in themselves a menace. The com- 
plete obliteration of the air space of the lung in pneu- 
monia by the inflammatory exudate or the compression 
of the lung and the great displacement of the heart by 
a massive pleural exudate, are examples, but no doubt 
we must be content with the thought that otherwise 
the man must have died long before from the direct 
effects of the bacteria. 

Inflammation which, as we see, is a local reaction, 
is commonly associated with a general reaction also of 
a defensive nature, fever. They are independent in 
the sense that there may be fever without any inflam- 
mation. They are so different that we are by no means 
forced to include fever in our conception of inflamma- 
tion but may think of it as an analogous or parallel 
reaction. In its complexity it also suggests a long 
evolution with the retention or survival of the most 
useful features and like inflammation, although its 
defects and its disturbing influence have long been 
uppermost in our minds, it is more and more clearly 

35 



recognised as a beneficial reaction somehow associated 
with immunisation and the limitation of injury. 

The whole range of phenomena which we know 
under the general heading immunity belong here also 
as reactions of living beings to injury developed in 
such a way as to render the body safe from that par- 
ticular injury in future. This safety cannot in nature 
be attained without suffering although we can cheat 
the disease of its penalties sometimes by artificial 
means. At best though, it is the successful struggle 
against the injury which fortifies the body against 
another such attack. Time will not permit us to dis- 
cuss this subject about which a whole literature has 
arisen. It is interesting in connection with inflamma- 
tion chiefly in that it is another member of the array 
of defensive reactions. 

With our present knowledge it is perhaps unjustifi- 
able to state that the process of inflammation itself 
brings into play the immune bodies which result from 
the introduction into the tissues of foreign proteins or 
protein poisons. That would be to assume that the 
fluid of the inflammatory exudate contains these 
immune substances in a degree effective as part of the 
mechanism of defense. This is hardly to be suggested 
in all the myriad examples of inflammation which 
result from some physical injury — it is hardly imagi- 
nable in the early stages of inflammation caused by 
bacteria in which stages the outpouring of fluid 
exudate is more profuse. In the late stages of a pro- 
tracted inflammation caused by bacteria it is clear 
that immunity is developed and may turn the tide of 
success in resisting the infection — it is even clear as 
Cross showed that during a long infection opsonins 
in the blood increase in such a way that phagocytosis 
is more effective than before. But in general while the 
reactions of immunity come readily to the aid of 

36 



inflammation they do not form an integral part of 
that reaction and at most we can only say that in 
inflammation the fluid exudate in addition to its dilut- 
ing and mechanical effect brings to bear upon the 
bacteria or upon the protein poisons the natural 
bacteriolytic and proteolytic ferments of the plasma 
and of the leucocytes and not except through the aid 
of a separate reaction the specific new formed immune 
bodies which arise after the lapse of time. 

Interesting in this regard is the intensified inflam- 
matory reaction in an allergic animal which has been 
sensitized by the introduction of some protein when 
the same protein is again brought into contact with 
the tissues. The tuberculin reaction in tuberculous 
animals is an example of this and so too is the flaring 
inflammation which follows the inoculation of tubercle 
bacilli in an animal which has survived an old tuber- 
culous infection. In these cases it seems probable that 
the readiness of the allergic tissues suddenly to decom- 
pose these proteins into toxic proteoses is a sufficient 
explanation of the greatly intensified injury with its 
appropriate reaction. But it is not quite so simple as 
this for Rossle in his recent experiments shows that 
the tissues react with eosinophile leucocytes or with 
lymphocytes when the sensitizing protein is again 
injected and that there are peculiar stases in the 
vessels, excessive oedema and evidences of shock. 

Regeneration and Repair 

Relation to Inflammation. — So far then we find in 
inflammation a response to injury carried out by the 
flushing of the widened capillaries in the local area 
and the pouring out of fluid and cellular exudate to 
which is added an inwandering of the. mononuclear 
phagocytic cells of the tissues which tend to clean up 
the devastated region. But this advent of leucocytes 

37 



and the accompanying leucocytosis in the general 
circulating blood as well as the swarming of the mono- 
nuclear cells suggests the necessity of a new formation 
of these cells. We cannot easily find the manufactory 
of the mononuclears but we have only to look at the 
bone marrow of the femur to find an intense multi- 
plication of its blood-forming elements in progress. 
Some message has been sent which stimulates it to 
this great activity — the function to which it is specifi- 
cally adapted, but still a new formation of cells in 
response to a demand which is really an essential part 
of inflammation. This touches at once upon the bitterly 
debated question as to the propriety of including in 
the conception of inflammation the new formation of 
tissue. To me it has always seemed that the idea of 
inflammation already outlined is complete and well 
rounded — that any new formation of fixed tissue 
elements, which is of course intertwined in any inflam- 
matory reaction following destruction of tissue, is 
really a separate and different kind of process, belong- 
ing more strictly to the conception of regeneration 
and concerned in this instance with the repair of the 
cells which were lost. If we transfer our attention to 
such processes of new formation of tissue as are found 
in the compensatory enlargement of half the liver 
when the other half is removed, or of one kidney when 
the other is extirpated, we have new growth without 
any trace of inflammatory reaction. Indeed the hyper- 
trophy of the heart or of any other functioning organ 
when more work is put upon it, illustrates this and 
unless we can show that the new growth of tissue 
which occurs in an inflamed area is a direct result of 
the injury and defensive in nature, it seems hardly 
incumbent upon us to include it within the limits of 
inflammation. 

But the very effort to assign reasons which would 

38 



make it necessary to group inflammation and new 
formation of tissue under one name shows how unim- 
portant it is to make sharp frames for each conception 
because they are after all rather arbitrary groups of 
phenomena. The recent literature is largely devoted 
to arguments as to the definition of inflammation — 
Aschoff would include in it every defensive reaction — 
others would abandon the term altogether. Practically 
all authors except perhaps Neumann and Borst include 
new formation of tissue under inflammation without 
any hesitation. Neumann separates them to some 
extent and Borst speaks of inflammatory new forma- 
tion as somewhat distinct from regeneration in general 
and cites many examples of chronic inflammatory pro- 
cesses in which excessive new* formation of tissue 
is indissolubly associated with inflammation, as in 
elephantiasis. He regards such inflammatory new 
formation as in the nature of organisation — the grow- 
ing into or about foreign or dead materials. This is 
not a direct result of a stimulus but an indirect one 
due to an increase in the function of these cells. 

Under any condition we are clear enough as to the 
phenomena themselves — the inflammatory vascular 
reaction which is directly responsible for the recog- 
nised cardinal symptoms, forms one convenient group ; 
the regenerative new formation of tissues in whatever 
place and for whatever purpose form another con- 
venient group. The latter occurs constantly without 
any participation of the former and there are also 
many examples of inflammation with little or no 
appreciable new formation of tissue (unless we include 
the leucocytosis). No compelling facts seem to exist 
which force us to associate the growth of tissue with 
the defensive inflammatory reaction and, therefore, 
for convenience sake it seems permissible and prefer- 
able to hold them separate as abstractions from the 

39 



complex mixture of phenomena which is usually found. 
Marchand in his most recent paper (1921) gives the 
following definition of inflammation. 

"We understand, therefore, by 'inflammation/ 'in- 
flammatory' a series of reactive processes on the part 
of the vessels and the tissues which after the action of 
injuries of physical, chemical and infectious character 
pursue an orderly course and in favorable cases lead 
to the abatement of the injury and thereby to healing 
(Biological definition). 

"Acute inflammation is initiated and characterised 
by local hyperemia, widening of the small vessels, 
irritative arterial hyperemia with increased blood 
stream through the part, upon which follow slowing 
of the circulation, paralysis and increased permeabil- 
ity of the walls of the small vessels, which with con- 
stant participation of the elements of the tissue lead 
to the formation of a coagulable exudate more or less 
rich in cells. 

"We define as chronic inflammatory processes those 
which proceed with continuous exudate formation and 
with conspicuous tissue growth, especially of the 
vessels and connective tissues and which either arise 
from acute inflammation or without this develop gradu- 
ally when there is protracted injury of the tissue." 

Healing. — The healing process depends upon a new 
formation of the cells of the tissue to replace those 
which have been destroyed and thus to make good a 
defect whose size is usually rapidly decreased by con- 
traction during the completion of this new formed 
tissue. Perhaps the simplest example is found in the 
healing of a wound with actual loss of tissue which 
must be filled up by new tissue. The injury in itself 
is sufficient even without infection to excite an inflam- 
matory reaction. Blood escapes upon the surface of 
the exposed tissue and clots, or if this be removed the 

40 



inflammatory exudate continues to escape and clot on 
this surface. Growth of tissue begins in due time by 
division of the cells a little way back from the actual 
surface or from the edge of the epidermis. New con- 
nective tissue cells are formed and sprouts from the 
capillaries whose ends have been interrupted in the 
wound and finally plugged by thrombi. Together these 
capillaries and fibroblasts thrust forward toward the 
surface, penetrating the overlying blood clot or the 
fibrin of the coagulated exudate and digesting it away. 
The leucocytes of the exudate and the mononuclear 
wandering cells are present in numbers and injury 
from persistent bacteria may cause a further exudate 
formation from the new capillaries, but gradually, 
except when the bacteria are very tenacious of life, 
the surface of the new tissue becomes clean and all the 
fibrin and cell refuse through which it has grown are 
removed. The tissue has a rough granular surface 
(granulation tissue) and is oedematous and infiltrated 
still with wandering cells. It is extraordinarily rich 
in blood vessels, soft and easily made to bleed but now 
very resistant to the further invasion of bacteria. 
Even before it reaches the level of the skin multipli- 
cation of epithelial cells pushes forward the edge of 
the epidermis and a thin bluish film of new epithelial 
cells creeps from every side over the granulation 
tissue, covering it smoothly. Then with this pro- 
tection the inflammation fades away, the fibroblasts 
and intercellular fibres increase while the capillaries 
diminish in number so that finally a dense scar of 
gradually increasing pallor is formed. It requires a 
long time before such a scar is reorganized by the 
ingrowth of nerves, the formation of papillae in a new 
corium, etc., and it is only the oldest scar that 
approaches the normal appearance of the original 
tissues at that site. Quite similar is the healing in the 

41 



peritoneum when two loops of intestine are glued 
together by fibrin after infection and injury and an 
acute peritonitis. Blood vessels and fibroblasts grow 
through the fibrin, eating it away and absorbing it 
until they meet and fuse with their fellows of the 
opposite side. Peritoneal lining cells cover on all sides 
this new fibrous adhesion which may be short and 
thick but sometimes mechanically stretched out into 
a thin veil-like sheet. 

Healing in a tissue where there has been necrosis of 
a mass of cells with diffuse surrounding inflammation 
proceeds in the same way as soon as the site is tenable 
for the new capillaries and fibroblasts. Often it goes 
in advance of this cleaning up and purification and the 
advancing capillaries are blocked and destroyed by 
the still present bacteria. Even when the way is cleared 
by the phagocytes and their ferments and the necrotic 
tissue liquefied and absorbed, there may be a cavity 
left filled with fluid, but the new cells by growing for- 
ward and drawing together, soon obliterate this 
cavity. Leucocytes may pass back into these capil- 
laries but often they have suffered such injuries that 
they themselves are swallowed and destroyed by other 
cells or liquefied by their ferments. 

Nature of Repair. — The outstanding problem at this 
stage is that of the reasons for the new formation of 
cells and the workmanlike repair of the defect. We 
have been able to find some sort of plausible reason 
for the widening of the vessels and the outward rush 
of leucocytes and fluid although it is true that we 
have not been able to explain these things on purely 
physical or chemical grounds but in each instance have 
left an element of irritability of the living cell which 
is a mystery. When we say that the leucocytes make 
haste toward bacteria or other irritants on account of 
a chemiotactic attraction, it is conceivable that some 

42 



day we may be able to explain this as a phenomenon 
of surface tension which is affected more and more 
strongly by the diffusing material as the leucocyte 
enters into zones of greater concentration, but this 
proves a rather inadequate explanation of the observed 
fact that a leucocyte may be gradually accustomed to 
some substance which at first repels it so that after- 
ward it is attracted. When we find that the tips of 
the lashes of endothelium which are to form blood- 
vessels meet precisely and unite like the ends of a 
tunnel bored by a skilful engineer from opposite sides 
of a river, we say once more that it is a chemiotactic 
process. It seems easier to believe that as Clark 
described it, they wave about until they touch each 
other and then unite. 

But when we come to consider the new growth of 
blood vessels, Of fibroblasts and of epithelium which 
serve to fill the gap, the mysteries are even more pro- 
found and we are forced to a conception of a fore- 
ordained plan which continues to control all growth 
not only in the individual but in all individuals of that 
species. It is as though all repairs were made by refer- 
ence to the original builders blueprints. The repairs 
may be awkwardly carried out but in the end it 
approaches the plan because the tissues are never con- 
tent but continue to modify the area of healing until 
its site can hardly be found and it is merged into the 
normal relations. Naturally this requires a long time 
and many people die with the restoration still incom- 
plete, but in adult life it is hard to find the point at 
which a bone was broken in childhood and the scars 
of slighter injuries are often more quickly obliterated. 
It seems that a very precise equilibrium of tissues is 
reached in the normal body. This is true from a func- 
tional point of view as everyone knows but it is also 
true structurally. The right side of the heart throws 

43 



out into the arteries of the lungs exactly the same 
number of drops of blood at each beat as the left side 
throws into the aorta and there is little doubt, although 
I have not the figures to show it, that the ratio of 
fibres in the wall of the right ventricle to those of the 
left is a mathematical constant. So, too, the relation 
of the number of cells in the liver to those in the 
kidneys is probably a constant and the loss of one 
hundred liver cells must be felt as a disturbance of 
equilibrium. This must be a functional equilibrium, 
but it may be maintained by a restoration of those cells 
to the proper number. It is possible, also, that aside 
from tissues which have such important chemical 
functions there may be a physical equilibrium in the 
supporting tissues so that when a stretch of fascia is 
interrupted by an injury, equilibrium is not restored 
until it is repaired and the normal tension re-es- 
tablished. 

Theories of Causes of Tissue Growth. — This idea, 
which may be applied in its details to every tissue in 
the body, is the basis for Weigert's conception of the 
reason for the new growth of tissue after injury. 
Virchow had assumed a formative stimulus exerted 
by the irritant directly upon the cell and causing it 
to grow. Weigert hotly contested the possibility of 
such an effect and claimed that in all cases the impul- 
sion to growth came from the disturbance of equi- 
librium due to the loss of other cells, the sense of 
defect or, in its simplest form (although this was more 
definitely the idea of Ribbert) the relaxation of the 
pressure or tension put upon the adjacent living cells 
which are capable of division and growth. But the 
power of growth itself was inherent in the cell and 
represented a part of the energy transmitted to it as 
an inheritance from the great store of energy of the 
fertilised ovum. Virchow thought of a direct chemical 

44 



or physical stimulus to growth. Such a stimulus could 
hardly be thought of as contributing the energy which 
is revealed in the actual growth — if not, it could only, 
like the trigger of a gun, let loose the energy of the 
cell — change its function to the extent of stirring it 
to absorb more nutrition and apply more energy to 
growth. It might even be regarded as the removal of 
an inhibition which prevented the cell from carrying 
on this natural absorption of nutrition, formation of 
new chromatin and cytoplasm and division. In this 
sense a formative stimulus is not very different from 
a disturbance of equilibrium since in both cases an 
inherent power of the cell is let loose. 

The practical difference in the application of these 
two ideas which still struggle for supremacy is that 
with cell growth the result of a chemical or physical 
formative stimulus, Virchow need not hesitate to con- 
ceive of the process of Cell division and growth pro- 
ceeding to the formation of any quantity of new tissue. 
Weigert ought to be at a loss for an explanation of 
any growth beyond that necessary to re-establish the 
equilibrium. 

But everyone knows that excessive growth of tissue 
occurs. Granulation tissue may grow far out of a heal- 
ing wound and project on the surface, an old pleurisy 
ends in a scarred mass all round the lung a centimetre 
thick, a cirrhotic liver may contain broad bands of 
dense fibrous tissue which fairly creak when cut 
through. Weigert was forced to assume that the 
response to the need of repairing the defect often over- 
shot the mark in simple healing and later repaired 
this fault by reducing the tissue to normal limits. The 
explanation of the thick scarred pleura is even more 
difficult but if it be attempted upon the idea that the 
persistence of bacteria frustrates each attempt at 
healing so that it soon comes to be a question of heal- 

45 



ing defects in new-formed tissue, and the layers pile 
up, we must still assume that each new healing over 
fills the actual defect — otherwise there would be no 
piling up of layers and only when the last layer was 
permanently laid would the original level be reached. 
In the case of the pleura this would be a pretty thin 
layer. 

On the whole it seems that the attempt at the 
orderly restoration of the body form in every detail is 
an underlying process which makes its influence felt 
ultimately — but that may be a different thing from 
that which causes the immediate new growth of tissue. 
The underlying tendency would replace the tissue as 
it was, the immediate new growth of tissue far more 
often substitutes something not quite as good — it 
repairs with the ever ready connective tissue. 

What are we to think about the new formation of 
tissue which is so often — almost regularly — interlaced 
with the phenomena of inflammation after an injury? 
Is it purely a response of the underlying tendency to 
make good the cells which have been destroyed? Is it 
due strictly to the disturbance of physical or functional 
equilibrium? In that case it ought to replace each 
tissue exactly and no more. But it substitutes in the 
interim a mass of fibrous tissue which can hardly be 
a response to the loss of functional equilibrium in 
areas previously composed of working epithelium, as 
in the liver. Must we then think that the injury acts 
as a direct stimulus to these bystanders among cells 
to stir them to growth or at least let loose their energy 
of growth as a mechanism of quick repair and pro- 
tection of the exposed injured area? Perhaps this 
fibrous tissue is always tending to grow to excess and 
is only held in check by the surrounding cells so that 
instead of a formative stimulus it is merely left free 
to grow. Or may we think of it all as merely a blind 

46 



response of the fibrous tissues and the blood vessels 
and the overlying epithelium to the tactile and 
chemical stimulus offered by fibrin and dead tissue 
through which, and over which, they grow. 

It is hard to decide and after all it seems a scho- 
lastic argument about a very small point which, in the 
end, may not depend on a very real difference between 
the views. 

Relation of Repair and Regeneration to Embryonic 
Development. — The actual process of growth under 
these disturbed conditions is, nevertheless, of great 
interest. When a cell is killed naturally all its 
functions cease but when it remains alive, though 
injured, and shows some of the retrogressive changes 
which we have already described, it is a question as to 
how far it is able to undertake the complex effort of 
absorbing new materials of nutrition and dividing into 
two. One sometimes finds mitoses in cells which lie in 
a zone which is exposed to injury and which themselves 
show inclusions of fat droplets which are supposed to 
indicate in such a case a retrogressive change. We are 
less surprised to find evidences of rapid growth in cells 
somewhat further removed from the line of injury. 
But any injury must impair in some way these cells 
although perhaps we may say that it only disturbs 
them. Borst thinks of three processes as characteristic 
of the cell : nutrition, multiplication, and its specific 
function. If, then, the disturbance impairs the specific 
function, the cell may still be even more ready to 
assimilate nutriment and to divide. But in general he 
assumes that assimilation and division are the direct 
outcome of increased function as seen very clearly in 
the rapid growth of a kidney when the other is 
removed, or in the hypertrophy of a heart when it is 
overworked. And he points out the impressive fact 
that no physical machine which we could imagine our- 

47 



selves constructing would have the unique property 
of growing and increasing its power or even of pro- 
ducing several new machines of equal power through 
being overworked. 

The power of the tissues to grow depends upon a 
vital property which our knowledge of physics and 
chemistry has not yet allowed us to explain. This 
property is present in perhaps the supreme degree in 
the fertilised ovum which is about to segment and as 
the segmentation proceeds its several elements are 
transmitted to successive generations of cells in 
decreasing intensity — the pow T er of assimilating nutri- 
ment persists, the power of multiplication rapidly 
decreases, the power of differentiation into specialised 
cells with different functions is quickly reduced to 
unipotence, or the ability to reproduce only its own 
kind. The ovum is totipotent but there is a gradual 
loss of the ability to differentiate until the cell becomes 
unipotent and unable to differentiate itself any further. 
But not all tissues are reduced to absolute unipotence 
from the state of multipotence which they enjoyed in 
the embryo, for there are some, such as the endothelial 
cells of the bone marrow, which in the adult are able 
to give rise to several kinds of blood cells. The very 
ability to multiply is better preserved here than else- 
where but there are also other zones of proliferation 
such as the Malpighian layer of the epidermis, which 
throughout life seems to be actively replacing cells 
which are lost from the surface. 

Phylogenetically the power of regeneration is dimin- 
ished and the regeneration of extensive and complex 
structures which occurs so readily in the lower animals 
is lost to us. But tissue can be reproduced by the 
multiplication of remnants of tissue of the same kind. 
So long as any of the unipotent differentiated tissue 
remains it can form more of the same kind but there 

48 



is little evidence of the formation of any highly differ- 
entiated tissue such as the cells of the liver or kidney 
from anything which had never reached that stage 
before the emergency demand for new tissue arose. 
Thus, it is extremely rare to find any satisfactory 
evidence of the development of new liver cells from the 
stumps of bile ducts although remnants of differenti- 
ated liver cells produce them in abundance. 

Tissues are thus able to regenerate without much 
new differentiation and the frequent references made 
to a return to the embryonic state in connection with 
the newly formed cells in the repair of an injury seem 
unjustified since these tissues apparently only repro- 
duce their kind without any return of a power of differ- 
entiation into cells of other specialised function. At 
least so it would appear although we are not quite 
certain that the new blood vessels of granulation tissue 
cannot once more assume the power of forming from 
their freshly grown endothelial cells new mononuclear 
wandering cells which may swell the host that we find 
collected there. 

The more highly differentiated and specialized in its 
function the cell, the less in general is its power of 
reproducing itself and it is for this reason that defects 
in voluntary muscle and heart muscle and in the brain 
are filled up by fibrous tissue, or neuroglia in the case 
of the brain, which is their only substitute for a long 
time. 

We are not interested here in the general subject of 
regeneration but only in so far as it has a bearing 
upon the completion of the fate of an injured area in 
which inflammation has played its part. 

Course op Inflammation in Various Infections and 

Other Injuries 

Let us examine then a few concrete examples of 
different effects of injury with inflammation or repair, 

49 



io see how these processes are illustrated and how they 
are interrelated. 

Pneumonia. — Acute lobar pneumonia caused by the 
invasion of the pneucococcus is the result of the direct 
injury of the epithelial cells which line the bronchi, 
the bronchioles and alveoli, and of the underlying 
connective tissue and capillary blood vessels. The 
response to this injury is, after the desquamation of 
some of the injured epithelium, the pouring out into 
the air spaces of a great quantity of fluid, leucocytes 
and red corpuscles with the rapid coagulation of this 
fluid. The affected part of the lung becomes consoli- 
dated. Various alterations occur in sequence in the 
color and consistency of the exudate, the red corpus- 
cles fade and the leucocytes become relatively more 
numerous. Through their digestive activities they dis- 
solve the whole exudate after the point is turned at 
which the protective immunization of the patient 
ensures recovery and the destruction of the bacteria. 
The liquefied exudate is partly removed by coughing, 
partly by absorption through the lymphatics and the 
restoration of the lung to normal is completed by 
the reformation of the epithelial cells which were 
destroyed. Otherwise there is practically no new forma 
tion of tissue and pneumonia of this character is a 
fairly pure example of inflammation very little inter- 
mixed with reparatory processes. But if anything 
delays for a long time the liquefaction of the exudate 
(and this may be due to an unusual flooding of the 
tissue with the antiferments of the blood) the clot 
becomes invaded by new vascular connective tissue, 
just as in the healing of a wound, and the air spaces 
of the lung permanently obstructed by this new tissue. 
Organisation in pneumonia is, therefore, not a favor- 
able outcome and seems to be prevented ordinarily by 
some process which has been explained by Kline as 

50 



the result of the compression of the blood vessels and 
the withholding from the area, of the blood which is 
rich in an antienzyme capable of preventing the solu- 
tion of the exudate. 

Abscess Formation. — An abscess is formed when 
bacteria, through remaining closely clumped together, 
radiate from a point a very concentrated destructive 
effect. Staphylococci often do this perhaps in virtue of 
this tendency to grow in a solid mass and are soon 
completely surrounded by dead and coagulated tissue 
The inflammatory reaction which arises on all sides 
sends its exudate of fluid and leucocytes toward this 
centre or core of dead tissue and liquefaction of the 
margin of the dead tissue and of the dying leucocytes 
occurs so that a cavity is formed, filled with pus in 
which the central core is isolated. If the abscess bursts 
or is laid open, the central dead mass which is still 
solid is removed together with most of the bacteria. 
The wall of the cavity is by this time a beginning 
granulation tissue through which leucocytes are still 
wandering and in which numerous large mononuclear 
phagocytes are lodged loaded with fragments of cells 
and fat globules. The ultimate fate of such a cavity is 
much like that of any open or infected wound. It is 
gradually cleaned and contracted and is filled up from 
the base by granulation tissue which forms a dense 
scar. But if a deep seated abscess is never opened the 
bacteria may in time be overcome by the fluids of the 
body and the exudate gradually inspissated and 
invaded by phagocytic cells and by granulation tissue 
so that ultimately a radiate scar is all that remains. 

Fate of Foreign Bodies in Tissues. — If, in an 
inflamed wound a fragment of foreign material 
remains, such as a piece of sponge or of gauze, the 
part played by leucocytes in combating this unusual 
obstruction to the healing of the wound is rather 

51 



temporary. They are soon relieved by the mononuclear 
phagocytes which apply themselves in great numbers 
to the task of removing the obstacle and swarm over 
every filament or particle. They attempt to engulf it 
but failing this spread their bodies about it and 
become in this process larger and multinucleated so 
that the filaments of gauze are soon seen to be clasped 
on all sides by huge foreign-body giant cells. With 
these a new granulation tissue associates itself and the 
foreign particles become encapsulated in a fibrous 
coating and thus eliminated from any direct contact 
with the rest of the tissue. Any foreign body is treated 
in this way but some prickly particles, such as lyco- 
podium grains or the siliceous bodies of diatoms seem 
to be particularly capable of calling out great numbers 
of these voracious cells. 

Inflammation, in Chronic Injection. — The process in 
a continually infected defect in the tissue results in a 
protracted repetition of the injury and of the lnflam 
matory reaction with a long continued persistence of 
the obstructions in the way of healing — even the new 
tissue which is formed in the process of healing is con- 
tinually injured and partly destroyed and must be 
reformed. The result in such cases is usually the con- 
densation of the scar tissue formed by whatever sur- 
vives of the granulation tissue while new granulation 
tissue arises on top of it. Layer after layer is thus 
laid down while the infected surface is still producing 
granulation tissue. Excessive tissue formation is thus 
a result of such longstanding infection. Excessive epi- 
thelial growth at the margins of the ulcer where its 
spread has been frustrated is of the same character. 

When the infection has lasted for many years, 
always accompanied by a smouldering inflammation, 
and especially where circulatory disturbances have 
been associated as in elephantiasis, the most colossal 

52 



excessive growths of tissue can occur, the whole sub- 
cutaneous connective tissue becoming enormously 
increased, often with added papillary outgrowths cov- 
ered by hyperplastic epithelium. Although this dis- 
ease has long been regarded as due to obstruction of 
the lymphatics by mature and larval filarice, the 
impression is gaining ground that much of it is really 
the result of streptococcal infections of the skin 
repeated through many years. 

Chronic Inflammations. — It is important at this 
point to refer to such processes as are familiar in the 
case of cirrhosis of the liver, chronic nephritis, chronic 
fibrous myocarditis, etc. All of these, although desig- 
nated by a name which involves the idea of inflamma- 
tion, are really hardly examples of inflammation. In 
each instance there is the direct and repeated effect 
of an injury with disturbance and destruction of the 
functioning tissue, the removal of which causes col- 
lapse of the framework of the organ and the replace- 
ment of the lost tissue by scar. Inflammation may, of 
course, be associated but in the more slowly and 
insidiously produced examples of cirrhosis or chronic 
nephritis with shrinkage of the kidney there is at no 
time any pronounced inflammatory process. In these 
cases the functional disturbance is usually dependent 
more upon direct alterations of the functioning cells 
which we cannot recognise with the microscope, than 
upon the loss of those cells which we can recognise. 
What we see in an old scarred liver or kidney is not 
so much the direct injury responsible for the impair- 
ment of function as the gaps in the tissue and the 
attempts at repair and regeneration of the tissue. 

But a great deal of new connective tissue is pro- 
duced and the question as to the stimulus for its 
formation remains, although we feel sure that it has 
a direct reparatory trend. 

33 



Tuberculosis and Allied Diseases. — This question is 
even more difficult in the case of certain specific bac- 
terial stimuli such as are found in tuberculosis, lep- 
rosy, syphilis, etc., in which there are peculiar forms 
of inflammation often with very little of the exudative 
process but with the calling out of many mononuclear 
phagocytes and later the extensive new formation of 
tissue. In some, as in the case of the miliary tubercle, 
the original injury and the infinitesimal primary 
inflammatory reaction have finally been demonstrated 
by Wechsberg for the support of Weigert's doctrine of 
primary injury and disturbance of equilibrium — but 
the rapid and more conspicuous response to the 
invasion of the tubercle bacilli is in the formation of 
a nodule of new tissue of peculiar type with concentric 
cells which may be of the nature of mononuclear 
wandering cells often with a multinucleated giant 
cell. 

Influence of Internal Secretions on Growth. — All 
who discuss the subject of new formation of tissue are 
impressed by the extraordinary growths which occur 
at puberty when the interstitial glands of the genital 
organs begin to circulate their secretion. Analogous 
to this are such tissue growths as are associated with 
pathological disturbances of the organs of internal 
secretion — hypophysis, adrenal, etc. — The tale of these 
is too long to be recounted here but in general in such 
a condition as acromegaly it appears that some 
chemical disturbance has directly stimulated a great 
new formation of tissue. So, too, in connection with 
great bronchiectatic cavities in the lungs from which 
decomposition products are absorbed, we see extra- 
ordinary new formation of bone and other tissue in 
the extremities. 

Influence of Chemicals on Growth and Repair. — 

Fischer's experiments with Sudan and Scharlach R. 

54 



which are now familiar, through the work of Davis 
and others, to all who deal with plastic surgery, show 
a remarkable effect upon the growth of epithelium and 
other tissues from the application of these fat soluble 
substances and the work of the Japanese who by rub- 
bing crude tar upon the skin have stirred up tumor 
like growths of epithelium is equally remarkable. 
Whether this should be ascribed to a removal of inhib- 
ition or to a direct stimulation it is scarcely yet possi 
ble to say. Even more interesting, although so common 
as to be overlooked, is the extraordinary effect of the 
growth of epithelial cells in a cancerous tumor in com- 
mandeering the new formation of a connective tissue 
stroma with blood vessels and lymph vessels and a per 
feet organisation. In this we have above all other 
examples, it seems, the acme of the phenomenon of 
the pathological new formation of tissue — only less 
wonderful and mysterious than the malignant growth 
of the epithelial cells themselves. 

We are confronted in these situations with the 
problems of living cells which are as yet insoluble for 
us. It is to be hoped that the researches of approach- 
ing years will go far to clear up this most mysterious 
process of the growth of tissue and the physical and 
chemical conditions which underly it. 

Review 

In retrospect, then, we feel that injury sufficiently 
intense to cause the destruction of cells and the irrita- 
tion or disturbance of others calls out the defensive 
mechanisms of the body, among which we recognise 
inflammation, fever and the production of immunity 
by its various means. Among these defensive reactions 
inflammation is a local but a well-rounded one carried 
out by the vascular tissues which arrange the flushing 
of the injured area and its flooding with the protective 

55 



elements of the blood. Leucocytes and wandering 
mononuclear cells are concentrated there and limit 
and annul the injury, finally removing the debris. 
They are necessarily manufactured in excess in the 
bone marrow and elsewhere to accomplish this duty 
when the injury is extensive. 

After this comes the process of new formation of 
tissue for repair of the injury but this seems a process 
belonging to a different category and carried out on 
other and different principles by quite different 
structural elements. Nevertheless, the two are so 
closely interlaced in any individual case that it 
requires an effort of thought to outline the abstraction 
inflammation from that of repair. 

BIBLIOGRAPHY 

1. Aschoff: Ziegler's Beitrage, 1921, LXVIII, I. 

2. Kreibich: Angioneurotische Entzundung Wien, 1905. 

3. v. Hansemann: Medizinische Klinik, 1920, XVI, 247. 

4. Marchand: Virch. Archiv, 1921, CCXXXIV, 245. 

Dtsch. Med. Woch., 1921, Nr. 40. 

5. Breslauer: Ctbl. f. Chir., 1920, XLVII, 1104. 

6. Jores: Frankf. Ztschr.f. Path., 1920, XXIII, 333. 

7. Clark: Am. J. Anat., 1919-20, XXVII, 221. 

8. Borst: Ziegler's Beitrage, 1919, LXIII, 725. 

9. Herxheimer: Ziegler's Beitrage, 1919, LXV, I. 

10. Lubarsch: Berl. Kl. Woch., 1917, Nr. 47. 

11. Groll: Verh. Dtsch. Path. Gesellsch., 1921. 

12. Neumann: Ziegler's Beitrage 1917-18, LXIV, J 



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